02
One-Pot Synthesis of Phenytoin Analogs in Solvent
free Conditions Via the Use of Pestle/ Mortar
Alireza Kiasat , Maryam Nikmanesh
Department of Chemistry , Shahid Chamran University , Ahwaz , Iran
Abstract
phenytoine derivatives were synthesized , via the pinacol
condensation with the reaction of 1,3- diphenyl- propane- 1,3- dione
(benzyl) analogs with urea or thiourea in presence of slica gel and
solid KOH as Solid phase catalyst in the mortar / pestle at room
temperatures. The reaction was completed at short reaction times
(approximately 15min) and pure products were obtained with high
yields (81-94%).
Key words: Phenytoin, Green Chemistry, Solvent free, Synthesis, Grinding
Introduction
Due to the growing green chemistry concern and influence of organic solvents on
environment as well as on human body, design of process that eliminate usage of
conventional organic solvents attracted the attention of synthetic organic chemists. Although
a number of modern solvent such as ionic liquid and water have been extensively studied
recently, but not usage of solvent at all is definitely best option [1].
Solid state organic synthesis, is an active area in recent research because of the good
dispersion of active reagent, immobilized on the porous solid support, enhanced selectivity
and reactivity, easier work up, facilitated scale up, cleaner , faster, higher yielding reactions,
reducing risk of polluting and explosions [2-7].
Heterocyclic compounds are an important units in variety of pharmacologically active
substances and treatment diseas[8]. In the other hand, synthesis of biologically active moiety
with high percentage yield as well as purity is one of the object of green chemistry, especially
in CNS acting drugs, this goal could be achieved by omitting interfering solvents [9].
In this view, we investigated, the 5,5-diphenyl-2,4-imidazolidinedione (phenytoin) nucleus, a
02 It used in wide range of biological activity such as anti arrhytmics [10], anticonvalsunt[11]
and antitumor[12] agents. Among this, it is commonly used as antiepileptic drugs. It is used
to treatment of tonic- clonic seizures and focal motor seizures [13], by reducing electrical
conductance among brain cells, by stabilizing the inactive voltage gated sodium channels .
Several, procedures for the synthesis of new hydantoin- like compounds were described
previously[14-16].
Due to follow our attention to solid state organic reactions, we report a novel synthesis of
phenytoin analogs from the easily accessible starting materials under solvent free conditions
using solid KOH and silica gel and 5-6 drop of DMF as catalyst, by grinding in a mortar
afforded the corresponding (1a).
H2N NH2 X
Solid KOH
Silica gel, 5-6 drop MDF grindig at room temperature
x= O or X
NH HN R3
O
X
R1 R2
R4 O
OH R1
R2
R4 R3
III(a-j)
O
O R1
R2
R4 R3
II(a-j)
Mechanism of phenytoin synthesis:
This reaction followed by benzoin condensation, self-condensation of aromatic aldehyde in
presence of NaCN , corresponding α- hydroxyl ketone (III) obtained. then, in presence of
concentrated nitric acid, oxidated to corresponding diketone (II) that due to intraction with
urea, hetrocyclic structure (4,5- dihydroxy – 2- imidazolone as intermediate) informed(IV)
and undergo pinacol rearrangment at acidic conditions and corresponding 5,5- diphenyl-
00
Ar- CH O
+ NaCN Ar C
H O -CN C -Ar HO CN C Ar H O C Ph CH CN OH O -Ar
- OH
-H O
H Ar C C
CN OH OH H Ar OH -Ar C O H C Ar OH (II) HNO3 Ar C O C O Ar (III)
H2N NH2 X N H H N X HO Ar Ar H2O+
(IV) N H H N X HO Ar
Ar + NH
H N Ar Ar X +HO
-H +
N H H N X O Ar Ar (I) EXPERIMENTAL
All chemicals were purchased from Sigma-Aldrich and were used without any purification.
Melting points are determined on Buchi 530. IR spectra were recorded on Perkin-Elmer
FTIR-1710 spectrophotometer usig KBR. The temperature of the reaction mixture was
measured through a non- contact infrared thermometer (AZ, Mini Gun type, Model 8868).
Preparation of 3- hydroxyl – 1,3- diphenyl propane 1- ompoone analogs (IIIa)
General procedure
A round bottom flask, was charged with 50 ml ethanol 96%, 30 ml (3.9 g, 25mmol) of
benzaldehyde, a solution of 2.5 g (38.3 mmol) sodium cyanide in 45 ml of distilled water
was added, reaction mixture was stirred for 1 hour, under reflux conditions. The process of
reaction was monitored by TLC. After complication of reaction, cooled the reaction mixture
to room temperature and then in an ice bath, solid precipitate was obtained and Collected
over in an Buchner funnel, It washed with distilled water (3-4 times) to remove excess
sodium cyanide, and recrystalized from ethanol 96%. Pour product obtained as white
crystals (26g, 86%).
02 Preparation of 1,3- diphenyl- propane- 1,3- dione analogs (IIa)
General procedure
Round- bottom flask equeiped with 20.2g (96.2 mmol ) of benzyl (IIIa) and 100 ml
concentrated nitric acid, 10g (125mmol) sodium cyanide as catalyst and heated at the reflux
conditions, for 90 min with stirring and gas trap, bring the solution to a gentle boil and
monitoring the reaction mixture with TLC. Formation of NO2 gas indicates oxidation of
compound ( IIa) when gas extracted completely, The solution was cooled and precipitate
was filtered off, recrystallized with 96% ethanol. Yield 72.9g (72%), pale Yellow crystal,
mp= 103 ˚C, previous report: mp= 102-104 ˚C
Preparation of 5,5- diphenyl imidazolidine 2,4- dione (Ia)
Classical method
A round bottom flask, was charged with 20.2 g ( 96.2 mmol) of benzyl, a 12.69 g (167mmol)
of urea in 40 ml of DMSO, 25ml of 1.2 aqueous KOH mixture were added under reflux
conditions for 2 hours. The process of reaction was monitored by TLC. After complication of
reaction, cooled the reaction mixture to room temperature and then in an ice bath, solid
precipitate was filtrated and the filtrate was acidified with HCl, the resulting precipitate was
collected , dried and recrystalized from ethanol 96%. Pour product was obtained as white
crystals (yield, 63%), m.p.= 295-296 ˚C
Solvent free Conditions:
A mixture of 20.2g ( 96.2 mmol ) of benzyl (IIa), 12.69g (167 mmol) urea, 11/2g (200 mmol)
Solid KOH, 50g Silica gel, 30 drop MDF, was ground by pestle and mortar at room
temperature for the period indicated in ( Table 1 ). After completion of reaction as indicated
by TLC [eluent:CCl4 / ether: 1:2 ]. The reaction mixture was worked- up in Dichloromethan.
Yield 83 g (83%), white crystal, mp=288- 295 ˚C .
5,5- di(4- Chloro phenyl)- imidazolidine- 2,4- dione (Ib)
As described for (Ia), 23.7g of 1,3- bis ( 4- Chloro- phenyl) propane- 1,3- dione (IIb) and
12.69g (167mmol) urea
02 As described for (Ia), 28.2g of 1,3- bis ( 4- Bromo- phenyl) propane- 1,3- dione (IIc) and
12.69g (167 mmol) of urea .
5,5- di(4- Cyano phenyl)- imidazolidine- 2,4- dione (Id)
As described for (Ia), 23.2g of 1,3- bis ( 4- Cyano- phenyl) propane- 1,3- dione (IId) and
12.69 g (167 mmol) of urea
5,5- di(2- Cl phenyl)- imidazolidine- 2,4- dione (Ie)
As described for (Ia), 23.7g of 1,3- bis ( 2- Cl- phenyl) propane- 1,3- dione (IIe) and 12.69g
(167 mmol) of urea
5,5- diphenyl- 2- thioxo- imidazolidin- 4- one (If)
The synthesis was performed as for (Ia) under solvent free conditions but using thiourea,
5,5- di (4- Chloro phenyl)- 2- thioxo- imidazolidin- 4- one (Ig)
As described for (If), 23.7g of 1,3- bis ( 4- Chloro- phenyl) propane- 1,3- dione (IIg) and
14.3g ( 165 mmol) of thio urea
5,5- di (4- Bromo- phenyl)- 2- thioxo- imidazolidin- 4- one (Ih)
As described for (If), 28.2 g of 1,3- bis ( 4- Bromo- phenyl) propane- 1,3- dione (IIh) and
14.3 ( 165 mmol) of thio urea .
5,5- di (4- Cyano- phenyl)- 2- thioxo- imidazolidin- 4- one (Ii)
As described for (If), 23.2 g of 1,3- bis ( 4- Cyano- phenyl) propane- 1,3- dione (IIi) and 14.3
( 165 mmol) of thio urea .
5,5- di (2- Chloro- phenyl)- 2- thioxo- imidazolidin- 4- one (Ij)
As described for (If), 23.7 g of 1,3- bis ( 2- Chloro- phenyl) propane- 1,3- dione (IIj) and
14.3g ( 165 mmol) of thio urea .
Mechanism of phenytoin synthesis:
This reaction followed by benzoin condensation, self-condensation of aromatic aldehyde in
presence of NaCN , corresponding α- hydroxyl ketone (III) obtained. then, in presence of
02 urea, hetrocyclic structure (4,5- dihydroxy – 2- imidazolone as intermediate) informed(IV)
and undergo pinacol rearrangment at acidic conditions and corresponding 5,5- diphenyl-
imidazolidine- 2,4- dione was obtained.
Ar- CH O
+ NaCN Ar C
H O -CN C -Ar HO CN C Ar H O C Ph CH CN OH O -Ar
- OH
-H O
H Ar C C
CN OH OH H Ar OH -Ar C O H C Ar OH (II) HNO3 Ar C O C O Ar (III)
H2N NH2 X N H H N X HO Ar Ar H2O+
(IV) N H H N X HO Ar
Ar + NH
H N Ar Ar X +HO
-H +
N H H N X O Ar Ar (I)
Table 1 : the time and yield of synthesized phenytoin
02
Conclusion
We report a novel synthesis of phenytoin analogs by grinding the reaction mixture under
solid phase conditions that involving, KOH, Silica gel without any solvent, so, it involves
easy work up, Other advantages of this method are less reaction time, high yield reaction is
carried out at room temperature and mild reaction conditions that make this procedure very
useful and environment friendly.
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